Compositional asymmetry is a defining feature of cellular membranes, controlling permeability, protein activity, cholesterol dynamics, and shape remodeling. This asymmetry can create a stress imbalance, with the two leaflets experiencing opposing tensions, though direct experimental measurement of leaflet stress remains challenging. Such a stress imbalance can compress one leaflet and trigger a fluid-to-gel phase transition, which reduces membrane fluidity and markedly increases bending rigidity. These phenomena raise a key question of how membranes respond mechanically before crossing the transition threshold, a regime that remains relevant to biological functions. Here, we combine extensive all-atom and coarse-grained molecular dynamics simulations to examine how stress asymmetry modulates membrane structure and mechanics near the transition point. Using POPE and DLPC bilayers as model systems, we find that moderate asymmetry induces transient gel-like domains that continuously form and dissolve, amplifying undulations and lowering bilayer rigidity. Beyond the gelation threshold, the trend reverses and the bilayer stiffens, resulting in a non-monotonic dependence of rigidity on asymmetry. Moreover, our results reveal distinct curvature preferences of fluid and gel phases. Extending this analysis to a multicomponent bacterial outer membrane, we demonstrate that stress asymmetry can trigger transient gel-like domain formation even in complex lipid mixtures. This provides a proof of principle that differential stress modulates membrane mechanics by inducing either softening or stiffening, complementing the effects of molecular composition. Our findings elucidate how cells might exploit the stress-curvature-phase coupling to tune membrane rigidity under near-physiological conditions.
Pirhadi et al. (Sun,) studied this question.